title: Antidiabetic and antisteatotic effects of the selective fatty acid synthase (FAS) inhibitor platensimycin in mouse models of diabetes.
abstract: Platensimycin (PTM) is a recently discovered broad-spectrum antibiotic produced by Streptomyces platensis. It acts by selectively inhibiting the elongation-condensing enzyme FabF of the fatty acid biosynthesis pathway in bacteria. We report here that PTM is also a potent and highly selective inhibitor of mammalian fatty acid synthase. In contrast to two agents, C75 and cerulenin, that are widely used as inhibitors of mammalian fatty acid synthase, platensimycin specifically inhibits fatty acid synthesis but not sterol synthesis in rat primary hepatocytes. PTM preferentially concentrates in liver when administered orally to mice and potently inhibits hepatic de novo lipogenesis, reduces fatty acid oxidation, and increases glucose oxidation. Chronic administration of platensimycin led to a net reduction in liver triglyceride levels and improved insulin sensitivity in db/+ mice fed a high-fructose diet. PTM also reduced ambient glucose levels in db/db mice. These results provide pharmacological proof of concept of inhibiting fatty acid synthase for the treatment of diabetes and related metabolic disorders in animal models.
authors.affiliation: Department of Diabetes and Obesity, Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Wu
authors.forename: Sheo B
authors.initials: SB
authors.lastname: Singh
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Christine C
authors.initials: CC
authors.lastname: Chung
authors.forename: Gino
authors.initials: G
authors.lastname: Salituro
authors.forename: Bindhu V
authors.initials: BV
authors.lastname: Karanam
authors.forename: Sang Ho
authors.initials: SH
authors.lastname: Lee
authors.forename: Maryann
authors.initials: M
authors.lastname: Powles
authors.forename: Kenneth P
authors.initials: KP
authors.lastname: Ellsworth
authors.forename: Michael E
authors.initials: ME
authors.lastname: Lassman
authors.forename: Corey
authors.initials: C
authors.lastname: Miller
authors.forename: Robert W
authors.initials: RW
authors.lastname: Myers
authors.forename: Michael R
authors.initials: MR
authors.lastname: Tota
authors.forename: Bei B
authors.initials: BB
authors.lastname: Zhang
authors.forename: Cai
authors.initials: C
authors.lastname: Li
mesh_terms: D000218:Adamantane / Q000627:therapeutic use*; D062365:Aminobenzoates / Q000627:therapeutic use*; D000813:Anilides / Q000627:therapeutic use*; D000818:Animals; D000890:Anti-Infective Agents / Q000627:therapeutic use; D003920:Diabetes Mellitus / Q000188:drug therapy*; D004195:Disease Models, Animal; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D005227:Fatty Acids / Q000096:biosynthesis; D005234:Fatty Liver / Q000188:drug therapy*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008099:Liver / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D010084:Oxidation-Reduction; D013261:Sterols / Q000096:biosynthesis
chemical_list: D062365:Aminobenzoates; D000813:Anilides; D000890:Anti-Infective Agents; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D013261:Sterols; D064429:Fatty Acid Synthases; D005947:Glucose; D000218:Adamantane; C510909:platensimycin